The current treatment for oral cancer is wide

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1 ORIGINAL ARTICLE RARE INVOLVEMENT OF SUBMANDIBULAR GLAND BY ORAL SQUAMOUS CELL CARCINOMA Tseng-Cheng Chen, MD, 1 Wu-Chia Lo, MD, 1 Jenq-Yuh Ko, MD, PhD, 1 Pei-Jen Lou, MD, PhD, 1 Tsung-Lin Yang, MD, 1,2 Cheng-Ping Wang, MD 1,2,3 1 Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. wangcp@ntu.edu.tw 2 Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan 3 Department of Otolaryngology, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan Accepted 2 October 2008 Published online 9 April 2009 in Wiley InterScience ( DOI: /hed Abstract: Background. The true involvement of the submandibular in primary oral cancer seems quite uncommon. Methods. We retrospectively reviewed the pathologic records of 342 patients with oral squamous cell carcinoma who underwent wide excision of primary oral cancer and simultaneous neck dissection from January 2000 to December Results. Of the 383 submandibular s, only 7 (1.8%) exhibited tumor involvement. Of them, 5 s were involved by direct extension from the primary tumor. One showed local invasion from an adjacent involved in level I and 1 was from intraular metastasis. All of these 6 tumors with submandibular involvement were T4 disease (p ¼.0003) and the neck nodal status on each was more than N2b (p <.0001). Conclusion. The patients with early-stage oral squamous cell carcinoma with preoperative N0 neck may be candidates for preservation of the submandibular. VC 2009 Wiley Periodicals, Inc. Head Neck 31: , 2009 Correspondence to: C.-P. Wang Contract grant sponsor: National Science Council of the Republic of China; Contract grant number: NSC B MY2. VC 2009 Wiley Periodicals, Inc. Keywords: submandibular ; oral cancer; xerostomia; neck dissection; saliva The current treatment for oral cancer is wide excision of the primary tumor and simultaneous neck dissection of various types such as selective or radical neck dissection, depending on the extent of neck involvement. Because the submandibular is located in level Ib, with 6 groups of s around/within the, and it is close to primary oral tumors, 1 the submandibular is usually removed regardless of the type of neck dissection performed. Because the submandibular s are responsible for about 70% to 90% of unstimulated salivary volume, 2,3 especially at night, removal of the submandibular as part of the neck dissection causes xerostomia of some degree, even though the patient does not receive postoperative radiotherapy. 2 However, the limited data available in the literature 4,5 indicate that true involvement of the submandibular in primary oral cancer is quite uncommon. Therefore, the submandibular might be innocent and Involvement of Submandibular Gland by Oral Cancer HEAD & NECK DOI /hed July

2 might be considered for preservation in surgical treatment of oral cancer to prevent xerostomia, especially when postoperative radiotherapy is not instituted. In this article, we want to answer the first basic question about the incidence of submandibular involvement by oral squamous cell carcinoma and then try to identify clinical risk factors that may predict submandibular involvement. PATIENTS AND METHODS This retrospective study reviewed the pathologic records of patients with oral squamous cell carcinoma who underwent wide excision of primary oral cancer and simultaneous neck dissection at the National Taiwan University Hospital from January 2000 to December The inclusion criteria for the study were (1) histopathologically confirmed squamous cell carcinoma, (2) primary site located in the oral cavity, and (3) no previous treatment for head and neck tumors. The exclusion criteria included patients with a previous history of other head and neck cancer, previous irradiation in the head and neck regions, a proven distant metastasis at presentation, or nonsquamous cell oral cancer. All surgical specimens including the primary tumor and the neck were submitted to the department of the pathology for permanent histopathological examination. The submandibular s were routinely examined grossly and microscopically. Grossly, the submandibular s were dissected out from the adjacent s and neck tissue. When the adjacent s were easily dissected from the and did not harbor malignant cells microscopically and the primary oral tumor was far from the grossly, several sections by 5 mm along the longest axis of the were microscopically examined. When the adjacent s harbored malignancy microscopically or any gross adhesions between adjacent tissue and the were noted, the submandibular nearby the involved s and the adhesion regions were microscopically examined in detail. The incidence of pathologic involvement of the submandibular by oral squamous cell carcinoma was calculated. In addition, potential risk factors such as sex, age, T classification, and N classification were evaluated. The TNM status of each tumor was reclassified according to the 2002 criteria of the American Joint Committee on Cancer. 6 All statistical analyses were performed using SPSS software for Windows, version 12.0 (SPSS, Chicago, IL). Associations between submandibular metastasis and several clinical factors were assessed using Fisher exact test. Statistical significance was set as p <.05. RESULTS The pathology reports of 342 patients were reviewed, including 302 men and 40 women, with a mean age of 50 years (range, years). Primary sites of oral cancers included the buccal mucosa (n ¼ 143, 41.81%), tongue (n ¼ 121, 35.38%), retromolar trigone area (n ¼ 22, 6.43%), alveolar ridge (n ¼ 20, 5.85%), floor of the mouth (n ¼ 17, 4.97%), hard palate (n ¼ 14, 4.09%), and lip (n ¼ 5, 1.46%). Of these patients, 301 underwent unilateral neck dissection including excision of the ipsilateral submandibular and 41 patients underwent bilateral neck dissection with excision of bilateral submandibular s, thus 383 submandibular s were available for pathologic examination. Of the 383 submandibular s, 7 (1.8%) exhibited tumor involvement, including 5 tumors with ipsilateral involvement and 1 with bilateral submandibular involvement. Four primary tumors were buccal cancer, with mandible extension in 3 and extension to the floor of the mouth in 1; and 2 primary tumors were gingival cancer, with extension of the floor of the mouth in 1. Five submandibular s were involved by direct extension from the primary tumor. One submandibular showed local invasion from an adjacent involved in level I and 1 was involved due to intraular metastasis (Table 1). All of these 6 tumors with submandibular involvement were T4 disease (p ¼.0003) and the neck nodal status in each was more than N2b (p <.0001) (Table 2). Three of the patients died of the disease within 6 months after treatment due to locoregional recurrence. Two patients have been alive for about 3 years and 1 patient has been alive for more than 6 years after definitive treatment. DISCUSSION From this series with 383 submandibular s examined, there was no case with 878 Involvement of Submandibular Gland by Oral Cancer HEAD & NECK DOI /hed July 2009

3 Table 1. Patterns of submandibular invasion by oral squamous cell carcinoma. No. of submandibular Incidence of invasion Ipsilateral submandibular 6/342 (1.75%) Contralateral submandibular 1/41 (2.43%) Direct invasion from primary 5 tumor Buccal cancer 4 1= 4 contralateral Mouth floor involved 2 Alveolar ridge involved 3 Gingival cancer (mouth floor 1 involved) Invasion from metastatic 2 Gingival cancer 1 Adjacent Buccal cancer (alveolar ridge involved) 1 Intraular submandibular involvement in T1-T3 or N0-N2a disease. Although all cases with submandibular involvement were T4 and N2b-N3, the incidence of submandibular involvement was only 6.67% in T4 disease and 8.22% in N2b-N3 disease. Therefore, submandibular involvement in oral squamous cell carcinoma is quite uncommon, especially in early stages. This is in accordance with previous reports. 4,5 From an anatomical viewpoint, the floor of the mouth, lower alveolar ridge, and tongue are the nearest to the submandibular. Theoretically, oral cancer involving these parts has the greatest chance of directly invading the ipsilateral submandibular. In Spiegel s series, 4 all of the 9 involved submandibular s, either invaded from the primary tumor directly or from the involved, were from ipsilateral cancers of the floor of the mouth, alveolar ridge, and tongue. In this series, there was no tongue cancer or cancer of the floor of the mouth involving the submandibular even though tongue cancer accounted for one third of our cases. Unlike previous reports, 4 buccal cancer was the most common oral cancer involving the submandibular, followed by cancer of the alveolar ridge in this series. This may be due to a higher incidence of locally advanced buccal cancer and much lower incidence of cancer of the floor of the mouth because of different chewing habits of the betel nut in this country. Despite this, all buccal cancers except 1 involving the submandibular clinically extended to either the alveolar ridge or the floor of the mouth. Interestingly, contralateral submandibular involvement from head and neck cancer has not been previously reported in the literature. 4 In this series, there was 1 locally advanced buccal cancer directly and bilaterally invading the submandibular s. Actually, this tumor was so huge that the ipsilateral parotid and sublingual s were involved simultaneously. In view of the mechanism of the invasion, most of the submandibular s were directly invaded by the primary tumor, which is in accordance with Spiegel s series 4 ; only 2 s were invaded by the metastatic in this series. Interestingly, 1 of them showed local invasion from a metastatic intraular of the submandibular, which is against the comment of Spiegel s series. 4 This finding proved the opinions of Bartels 7 and DiNardo, 1 who noted the existence of lymph nodes within the submandibular and believed that they account for 1 mechanism of tumor involvement of the although it is rare. What does this rare occurrence of submandibular involvement by oral squamous cell carcinoma imply in clinical practice? Because saliva enhances taste, speech, and swallowing and facilitates irrigation and lubrication of the oral cavity, salivary dysfunction impairs mastication, deglution, and gustatory functions, and results in dental caries and dry, painful Table 2. Clinical factors predicting submandibular invasion. Variables Positive submandibular p value Age NS 45 y 1/110 (0.90%) >45 y 5/232 (2.15%) Sex NS Male 4/302 (1.3%) Female 2/40 (5%) T classification.0003 T1þT2þT3 0/252 (0%) T4 6/90 (6.67%) N classification <.0001 N2a 0/269 (0%) N2b 6/73 (8.22%) Abbreviation: NS, not significant. Involvement of Submandibular Gland by Oral Cancer HEAD & NECK DOI /hed July

4 ulcerative oral mucosa. 2,4,8 Among the major salivary s, the submandibular produces about 70% to 90% of unstimulated salivary volume, especially during sleep. 2,3 Therefore, about one third of submandibular- resection patients reported xerostomia and impaired quality of life, particularly complaining of nocturnal xerostomia. 2 Although there are many therapies for xerostomia including synthetic saliva, gustatory stimulants, autologous saliva storage, acupuncture, electrostimulation, and various medi- cations, none of them can adequately improve quality of life, and some are associated with side effects. 4,9 If the lymph nodes around the submandibular can be removed with preservation of the functional, xerostomia and complications associated with saliva deficiency will be avoided, especially in early-stage oral cancers without expected postoperative radiotherapy. Given the findings of the present series, because T4 tumors positively predicted submandibular invasion and no T1-3N0 tumors involved the submandibular, patients with oral cancer at T1- T3N0 might be candidates for preservation of the submandibular during neck dissection for xerostomia prevention if section margin of the primary tumor is adequate. From the experiences of neck dissection for head and neck cancers and simple excision of the submandibular for other benign diseases, it is not difficult to dissect the adjacent tissue and lymph nodes from the submandibular without presence of the tumor nearby. The 4 groups of the s around the submandibular including preular, postular, prevascular, and postvascular groups, which are the more consistent and draining nodes of the oral cancer, are easily dissected from the. 1 It is somewhat difficult to dissect the deep group located between the and the mylohyoid muscle with preservation of the, but may be still doable by means of submandibular transfer technique. 10 It is really impossible to dissect the intraular s with preservation of the, but fortunately, this group is rarely present and involved by cancer. 1 When any suspicious metastasis or close contact between tumor and the was noted during neck dissection, the must be oncologically removed. Despite it is technically doable, this still needs further evaluation for feasibility and the potential risk for locoregional recurrence before this conservative approach is instituted. Although no submandibular invasion was noted in N1-N2a tumors in our review, preservation of the submandibular is not suitable for the patients with the preoperative presence of positive cervical even though the positive nodes were located outside of the level I as most of these patients might require postoperative adjuvant radiotherapy, which further leads to dysfunction of the remaining submandibular. Clark s series 11 found that sublingual invasion was not an adverse prognostic factor for local recurrence or survival. To date, no studies have addressed the prognostic value of submandibular invasion. 4 This is not evaluable in this present series because of the small sample size. Although 3 patients died of disease within 6 months after treatment, aggressive treatment for this subgroup of oral cancer is still valuable because the other 3 patients in this series have lived disease-free for more than 3 years. CONCLUSION Submandibular involvement by oral squamous cell carcinoma is quite rare, especially in the early stages. Locoregionally advanced T4 or N2b-N3 tumors positively predict the presence of submandibular invasion, especially in cases of buccal cancer and cancer of the alveolar ridge in this series. The patients with earlystage oral squamous cell carcinoma with preoperative N0 neck might be candidates for preservation of the submandibular during neck dissection. Further prospective study is needed to demonstrate the findings from this retrospective study. REFERENCES 1. DiNardo LJ. Lymphatics of the submandibular space: an anatomic, clinical, and pathologic study with applications to floor-of-mouth carcinoma. Laryngoscope 1998; 108: Jacob RF, Weber RS, King GE. Whole salivary flow rates following submandibular resection. Head Neck 1996;18: Saarilahti K, Kouri M, Collan J, et al. Sparing of the submandibular s by intensity modulated radiotherapy in the treatment of head and neck cancer. Radiother Oncol 2006;78: Spiegel JH, Brys AK, Bhakti A, Singer MI. Metastasis to the submandibular in head and neck carcinomas. Head Neck 2004;26: Involvement of Submandibular Gland by Oral Cancer HEAD & NECK DOI /hed July 2009

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